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Abstract Although lung cancer patients harboring EGFR mutations benefit from treatment with EGFR‐tyrosine kinase inhibitors (EGFR‐TKI), most of them rapidly relapse. RHOB GTPase is a critical player in both lung carcinogenesis and the EGFR signaling pathway; therefore, we hypothesized that it could play a role in the response to EGFR‐TKI. In a series of samples from EGFR‐mutated patients, we found that low RHOB expression correlated with a good response to EGFR‐TKI treatment while a poor response correlated with high RHOB expression (15.3 versus 5.6 months of progression‐free survival). Moreover, a better response to EGFR‐TKI was associated with low RHOB levels in a panel of lung tumor cell lines and in a lung‐specific tetracycline‐inducible EGFRL858R transgenic mouse model. High RHOB expression was also found to prevent erlotinib‐induced AKT inhibition in vitro and in vivo. Furthermore, a combination of the new‐generation AKT inhibitor G594 with erlotinib induced tumor cell death in vitro and tumor regression in vivo in RHOB‐positive cells. Our results support a role for RHOB/AKT signaling in the resistance to EGFR‐TKI and propose RHOB as a potential predictor of patient response to EGFR‐TKI treatment.